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Clinical Cancer Research : An Official... Dec 2021PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic...
PURPOSE
PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic cancers. This study evaluated the safety and efficacy of second-line treatment with veliparib and mFOLFIRI versus FOLFIRI (control) for metastatic pancreatic cancer.
PATIENTS AND METHODS
This randomized phase II clinical trial led by the SWOG Cancer Research Network enrolled patients between September 1, 2016 and December 13, 2017. The median follow-up was 9 months (IQR 1-27). and homologous recombination DNA damage repair (HR-DDR) genetic defects were tested in blood and tumor biopsies. Patients received veliparib 200 mg twice daily, days 1-7 with mFOLFIRI days 3-5, or FOLFIRI in 14-day cycles.
RESULTS
After 123 of planned 143 patients were accrued, an interim futility analysis indicated that the veliparib arm was unlikely to be superior to control, and the study was halted. Median overall survival (OS) was 5.4 versus 6.5 months (HR, 1.23; = 0.28), and median progression-free survival (PFS) was 2.1 versus 2.9 months (HR, 1.39; = 0.09) with veliparib versus control. Grade 3/4 toxicities were more common with veliparib (69% vs. 58%, = 0.23). For cancers with HR-DDR defects versus wild-type, median PFS and OS were 7.3 versus 2.5 months ( = 0.05) and 10.1 versus 5.9 months ( = 0.17), respectively, with FOLFIRI, and 2.0 versus 2.1 months ( = 0.62) and 7.4 versus 5.1 months ( = 0.10), respectively, with veliparib plus mFOLFIRI.
CONCLUSIONS
Veliparib plus mFOLFIRI did not improve survival for metastatic pancreatic cancer. FOLFIRI should be further studied in pancreatic cancers with HR-DDR defects.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Humans; Pancreatic Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34580114
DOI: 10.1158/1078-0432.CCR-21-1789 -
Cancer Medicine Dec 2014Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of...
Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥ 50% reduction in IC50 ) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC = 0.672; P = 0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Cell Line, Tumor; Chemoradiotherapy; Cisplatin; Drug Synergism; Etoposide; Humans; In Vitro Techniques; Lung Neoplasms; Mice; Mice, Nude; Poly(ADP-ribose) Polymerase Inhibitors; Random Allocation; Small Cell Lung Carcinoma; Xenograft Model Antitumor Assays
PubMed: 25124282
DOI: 10.1002/cam4.317 -
JCO Precision Oncology 2021Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic...
UNLABELLED
Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring / mutations, but the relative efficacy of PARP inhibition in - versus -altered mCRPC is understudied.
METHODS
We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with /-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among - versus -altered mCRPC.
RESULTS
A total of 123 patients (13 and 110 ) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. patients were more likely to have metastatic disease at presentation (69% 37%; = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% 46%; = .78) in both groups. patients had more monoallelic (56% 41%; = .49) and concurrent (55% 36%; = .32) mutations. PSA responses in - versus -altered patients were 23% versus 63%, respectively ( = .01). patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent mutation were associated with PARP inhibitor sensitivity.
CONCLUSION
PARP inhibitor efficacy is diminished in - versus -altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent alterations in the group.
Topics: Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Germ-Line Mutation; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; United States
PubMed: 34778690
DOI: 10.1200/PO.21.00070 -
Cancer Chemotherapy and Pharmacology Apr 2020Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents...
Phase I and pharmacokinetic study of veliparib, a PARP inhibitor, and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up.
OBJECTIVE
Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients.
METHODS
Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1-14 with PLD 40 mg/mg on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added.
RESULTS
44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID.
CONCLUSIONS
The RP2D is 200 mg veliparib BID on days 1-14 with 40 mg/m PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Doxorubicin; Female; Follow-Up Studies; Genital Neoplasms, Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Glycols; Prognosis; Survival Rate; Tissue Distribution; Triple Negative Breast Neoplasms
PubMed: 32055930
DOI: 10.1007/s00280-020-04030-2 -
Annals of Oncology : Official Journal... Oct 2015Veliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Veliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models.
PATIENTS AND METHODS
In this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).
RESULTS
Patients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0-5.5), 3.6 (1.9-4.1), and 2 (1.9-3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0-13.1), 13.6 (11.4-15.9), and 12.9 (9.8-14.3) months, respectively; ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively.
CONCLUSIONS
Median PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Benzimidazoles; Brain Neoplasms; Dacarbazine; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Survival Rate; Temozolomide; Young Adult
PubMed: 26202595
DOI: 10.1093/annonc/mdv308 -
Breast Cancer Research and Treatment Apr 2023Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly...
A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).
BACKGROUND
Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC).
METHODS
Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1.
RESULTS
Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%.
CONCLUSION
Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.
Topics: Humans; Female; Carboplatin; Paclitaxel; Breast Neoplasms; Triple Negative Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Anemia
PubMed: 36853577
DOI: 10.1007/s10549-023-06889-0 -
Clinical Cancer Research : An Official... Jun 2016Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA...
PURPOSE
Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.
EXPERIMENTAL DESIGN
A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m(2) day 1) and vinorelbine (25 mg/m(2) days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.
RESULTS
Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1-6.7).
CONCLUSIONS
Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation-associated breast cancer. Clin Cancer Res; 22(12); 2855-64. ©2016 AACR.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; BRCA2 Protein; Benzimidazoles; Cisplatin; DNA Repair; Disease-Free Survival; Female; Humans; Middle Aged; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Triple Negative Breast Neoplasms; Ubiquitin-Protein Ligases; Vinblastine; Vinorelbine
PubMed: 26801247
DOI: 10.1158/1078-0432.CCR-15-2137 -
Cancer Chemotherapy and Pharmacology Aug 2019Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling.
PURPOSE
Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling.
METHODS
The effects of time on the concentration-dependent cytotoxicity of approved and investigational agents [300 compounds] were examined in the NCI60 cell line panel in 2D at 2, 3, 7 and in 3D 11 days.
RESULTS
There was a moderate positive linear relationship between data from the 2-day NCI60 screen and the 3-, 7- and 11-day and a strong positive linear relationship between 3-, 7- and 11-day luminescence screen ICs by Pearson correlation analysis. Cell growth inhibition by agents selective for a specific cell cycle phase plateaued when susceptible cells were growth inhibited or killed. As time increased the depth of cell growth inhibition increased without change in the IC. DNA interactive agents had decreasing ICs with increasing exposure time. Epigenetic agents required longer exposure times; several were only cytotoxic after 11 days' exposure. For HDAC inhibitors, time had little or no effect on concentration response. There were potency differences amongst the three BET bromodomain inhibitors tested, and an exposure duration effect. The PARP inhibitors, rucaparib, niraparib, and veliparib reached ICs < 10 μM in some cell lines after 11 days.
CONCLUSIONS
The results suggest that variations in compound exposure time may reflect either mechanism of action or compound chemical half-life. The activity of slow-acting compounds may optimally be assessed in spheroid models that can be monitored over prolonged incubation times.
Topics: Antineoplastic Agents; Cell Line, Tumor; Humans
PubMed: 31102023
DOI: 10.1007/s00280-019-03863-w -
Therapeutic Advances in Medical Oncology 2021To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative,...
Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline / mutations and hormone receptor status from the phase-3 BROCADE3 trial.
PURPOSE
To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline (g)-associated breast cancer defined by hormone receptor (HR) and g/ mutation status.
PATIENTS AND METHODS
In this phase-3, double-blind, placebo-controlled trial, patients ( = 509) with advanced HER2-negative breast cancer and g mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and g mutation status were prespecified.
RESULTS
In the intention-to-treat population, there were similar proportions of patients with g g mutations (51% 49%) and HR+ disease triple-negative breast cancer (TNBC) (52% 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), = 0.013; TNBC: 16.6 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), = 0.052; g: 14.2 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), = 0.073; g: 14.6 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% 15.3%; TNBC, 40.4% 25.0%) and 3 years (HR+, 17.5% 8.6%; TNBC, 35.3% 13.0%) in all subgroups. g status () did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile.
CONCLUSION
Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by g g mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the g g and HR+ TNBC subgroups.
TRIAL REGISTRATION
NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.
PubMed: 34917174
DOI: 10.1177/17588359211059601 -
Cancer Chemotherapy and Pharmacology Feb 2019Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in...
PURPOSE
Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design.
METHODS
Population pharmacokinetic analysis was performed using Phoenix NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CL), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival.
RESULTS
A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CL and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure.
CONCLUSIONS
Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure-safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure-efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit-risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Leukemia, Myeloid, Acute; Male; Maryland; Middle Aged; Models, Statistical; Mucositis; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Temozolomide; Tissue Distribution; Young Adult
PubMed: 30456480
DOI: 10.1007/s00280-018-3731-4